In general, 5-HT4 receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease (GERD), gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia (FD), irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, gastritis, nausea, central nervous system disease, Alzheimer's disease (AD), cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, and apnea syndrome (See NPL 1; NPL 2; NPL 3; NPL 4; NPL 5; NPL 6; and NPL 7).
It is clear that the drugs with 5-HT4 receptor agonistic activity act as a prokinetic agent.
However the tissue specific activity in the upper or lower gastrointestinal tract has also been shown in 5-HT4 agonists such as cisapride, mosapride, prucalopride and tegaserod. Namely, mosapride and cisapride selectively enhanced upper gastrointestinal (GI) motility rather than lower GI motility, which resulted in being on the market as prokinetic agents.
On the other hand, prucalopride (NPL 8) and tegaserod (NPL 9) enhanced lower GI motility, which resulted in as the clinical use of constipation and/or constipation-predominant IBS (C-IBS). In addition, prucalopride (NPL 8) has been suggested to selectively stimulate colonic transit in healthy humans without altering gastric empting or small bowel transit (NPL 10).
Further, velusetrag (TD-5108) (NPL 11) and naronapride (ATI-7505) (NPL 12) which are being developed are falls in the constipation categories.
In medial front, a large population of patients with functional bowel disorders have frequently overlapping symptoms that affect both the upper and lower GI tract. Actually, IBS is frequently seen in association with GERD. Unfortunately there are no drugs having both upper and lower GI motilities in a same extent. Therefore, such an ideal drug showing stimulatory effects on both upper and lower GI motilities in a single administration is highly desired in many patients with GI diseases.
The present inventors in order to solve the problems as above have discovered that Compound A with 5-HT4 agonism exerts stimulatory effects on antral (upper) and colonic (lower) motility at the same dose. Therefore, this invention relates to the first example of the compound which demonstrates stimulatory effects both upper and lower GI motilities clearly in a same extent. In addition, the effects on GI motility of Compound A are much higher (more than 100 times) than those of other 5-HT4 agonists as shown in the working examples described in this specification. These profiles show that Compound A is valuable and feasible alternative to other prokinetic agents for patients suffering from functional constipation and C-IBS with upper GI symptoms such as dyspepsia or heartburn.